The present invention relates to 3-oxopropane-1-sulphonic acids and sulphonates, optionally in enantiomerically enriched form. The invention further relates to the use or enantiomerically enriched 3-oxopropane-1-sulphonic acids and sulphonates in the resolution or mixtures or enantiomers, for instance racemic mixtures. The invention relates in particular to (d)- and (l)-enantiomers of 3-oxopropane-1-sulphonic acids of general formula I or a salt thereof: 
wherein R1 and R2 each independently represent a (cyclo)alkyl, an aryl, an aralkyl or an alkaryl group, wherein the groups optionally contain one or more heteroatoms, for instance O, S or N or wherein R1 and R2 together with the C-atoms to which they are attached and the intermediate C-atom form a 5-8 membered ring which may contain one or more, for instance 1-4, preferably 1-2 heteroatoms, with an ee  greater than 80%, preferably  greater than 90%, in particular  greater than 95%. The invention relates more in particular to 1,3-diphenyl-3-oxopropane-1-sulphonic acids of general formula I or a salt thereof, in particular the (d)- and (l)-enantiomers of these compounds, wherein R1 and/or R2 represent a phenylgroup, optionally substituted with one or more, in particular 1-5, groups R3, wherein the groups R3 each independently represent H, halogen, hydroxy, a (cyclo)alkyl, aryl, alkaryl, aralkyl, (cyclo)alkoxy, aryloxy, amido, amino, nitro, acyl, carboxyl, aryloxycarbonyl, thiol or thioether group. Preferably R1 and R2 both represent an optionally substituted phenyl group.
It is known that sulphonic acids are strong acids and that such compounds could facilitate complex formation, in particular salt formation, in the resolution of mixtures of enantiomers (i.e. racemic mixtures or mixtures with a certain enantiomeric excess). A number of enantiomerically enriched sulphonic acids are known to be useful resolving agents, for instance camphor sulphonic acid (K. J. Brown, M. S. Berry, J. R. Murdoch, J. Org. Chem. 50, 4345, 1985; R. Dumont, A. Brossi, J. V. Silverton, J. Org. Chem. 51, 2515, 1986) and phenylethane sulphonic acid (R. Yoshioka, O. Ohtsuki, M. Senuma, T. Tosa, Chem. Pharm. Bull. 37, 883, 1989; E. J. Corey, K. A. Cimprich, Tetrahedron Lett. 33, 4099, 1992; R. Yoshioka, M. Tohyama, O. Ohtsuki, S. Yamada, I. Chibata, Bull. Chem. Soc. Jpn. 60, 649, 1987; R. Yoshioka, O. Ohtsuki, T. Da-Te, K. Okamura, M. Senuma, Bull. Chem. Soc. Jpn. 67, 3012, 1994). In Tetrahedron Lett. 33, 4099, 1992 Nobel prize winner Prof. E. J. Corey reports that chiral sulphonic acids are difficult to prepare. Chiral sulphonic acids would be very suitable in particular for the resolution of racemic mixtures of amines and amino acids (R. Yoshioka, O. Ohtsuki, T. Da-Te, K. Okamura, M. Senuma, Bull. Chem. Soc. Jpn. 67, 3012, 1994).
The present invention now provides resolving agents, which can be easily prepared and, therefore, are readily accessible.
Examples of 1,3-disubstituted-3-oxopropane-1-sulphonic acids and sulphonates (these derivatives are derived from the xcex1,xcex2-unsaturated carbonyl compounds of the type 1,3-disubstituted-2-propene-1-one; the 1,3-diphenyl-2-propene-1-one derivatives are known as xe2x80x9cchalconesxe2x80x9d) or related compounds are known in the literature.
1,3-disubstituted-3-oxopropane-1-sulphonic acids and sulphonates and more particularly 1,3-diaryl-3-oxopropane-1-sulphonic acids and sulphonates, can be prepared by addition of sodium bisulphite to the Cxe2x95x90C bond of the corresponding xcex1,xcex2-unsaturated ketones (E. Knoevenagel, Ber. 31, 4038, 1904; K. H. Pfoertner, Helv. Chim. Acta 63, 664, 1980) according to the general reaction equations: 
where MHSO3 stands for, for instance, sodium or potassium bisulphite.
In the literature the applicant has found the following compounds:
3-(2-hydroxyphenyl)-1-(4-hydroxy-3-methoxyphenyl)-3-oxopropane-1-sulphonic acid (a),
1-(3,4-dimethoxyphenyl)-3-(4-hydroxy-3-methoxyphenyl)-3-oxopropane-1-sulphonic acid (b),
1-(3,4-dimethoxyphenyl)-3-(2-hydroxy-3-methoxy)-3-oxopropane-1-sulphonic acid (c),
barium 1-(3,4-dimethoxyphenyl)-3-(2-hydroxy-3-methoxy)-3-oxopropane-1-sulphonate (d),
1-phenyl-3-(2-hydroxyphenyl)-3-oxopropane-1-sulphonic acid (e),
sodium 1-phenyl-3-(2-hydroxyphenyl)-3-oxopropane-1-sulphonate (f),
1-phenyl-3-(2-hydroxy-3-methoxy-5-methylphenyl)-3-oxopropane-1-sulphonic acid (g),
sodium 1-phenyl-3-(2-hydroxy-3-methoxy-5-methylphenyl)-3-oxopropane-1-sulphonate (h)
1-phenyl-3-(4-hydroxy-3-methoxyphenyl)-3-oxopropane-1-sulphonic acid (i),
sodium 1-phenyl-3-(4-hydroxy-3-methoxyphenyl)-3-oxopropane-1-sulphonate (j),
sodium 1,3-diphenyl-3-oxopropane-1-sulphonate (k),
sodium 3-(p-chlorophenyl)-1-(2-pyridyl)-3-oxopropane-1-sulphonate (1),.
sodium 3-(p-chlorophenyl)-1-(3-pyridyl)-3-oxopropane-1-sulphonate (m).
sodium 3-(p-chlorophenyl)-1-(4-pyridyl)-3-oxopropane-1-sulphonate (n), and
sodium 3-(p-methoxyphenyl)-1-(4-pyridyl)-3-oxopropane-1-sulphonate (o).
Compounds (a) and (b) are described in O. Dahlman, K. Maanson, J. Wood Chem Technol. 16, 47, 1996 (xe2x80x9cAnalysis of low molecular weight lignin-derived sulphonates by capillary zone electrophoresisxe2x80x9d). Compounds (c) and (d) are described in H. Richtzenhuin, B. Afredsson, Ber. 89, 378, 1956. Compounds (e) and (f) are described in H. Richtzenhuin, Ber. 72, 2152, 1939, and in K. Kratzl, H. Dxc3xa4ubner, Monatsh. Chem. 78, 376, 1948. Compounds (g) and (h) are described in M. F. Browne, R. L. Shriner, J. Org. Chem. 22, 1320, 1957. Compounds (i) and (j) are described by K. Kratzl, H. Daubner, in Ber. 77, 519, 1944 and Ber. 79, 895, 1946. Compounds (k)-(o) are described in K. H. Pfoertner, Helv. Chim. Acta 63, 664, 1980 (xe2x80x9cSubstituted alkyl sulphonates by addition of sodium hydrogensulphite to chalconesxe2x80x9d). Organic salts of such sulphonic acids are described by S. Rachwal, Zesz. Nauk. Uniw. Jagiellon, Pr. Chem. 32, 93, 1989 (xe2x80x9cAddition of amine hydrosulphites to vinyl ketones. Conformation of the gamma-oxoalkanesulphonate anionsxe2x80x9d). However, in the above-mentioned literature sources only the chemical composition of the compounds is disclosed without any suggestion of chirality or enantiomerical enrichment.
The present invention therefore relates to a (d)- or (l)-enantiomer of a sulphonic acid of general formula I or a salt thereof wherein R1 and R2 are as defined above.
Suitable examples of R1 and R2 are, for instance, a C1-C8 alkyl or a C3-C12 cycloalkyl group, a 6-ring aryl group, a C7-C12 alkaryl group, a C7-C12 arylalkyl group, a C4 or a C5 heterocycloalkyl or C4 or C5 heteroaryl group, a C5-C12 heterocycloalkyl or C5-C12 heteroarylalkyl group or a C5-C12 alkylheterocycloalkyl or C5-C12 alkylheteroaryl group, in particular methyl, ethyl, n- and i-propyl, n-, s- and t-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 1-naphthyl, o-, m- and p-methylphenyl, 2,4,6-trimethylphenyl, p-(t-butyl)phenyl, phenylmethyl, 2-phenylethyl, N-, O-and/or S-containing, unsaturated or saturated rings, in particular five or six rings for instance thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isothiazolyl, pyrrolidinyl, pyrrolinyl, isoxazolyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl and piperazinyl.
Preferably R1 and/or R2 represent a substituted or an unsubstituted aryl group. When R1 and/or R2 is a substituted aryl group, R1 and/or R2 has 1, 2, 3, 4 or 5 substituents R3, wherein preferably, the groups R3 each independently represent halogen, hydroxy, a (cyclo)alkyl, aryl, alkaryl, aralkyl, (cyclo)alkoxy, aryloxy, amido, amino, nitro, acyl, carboxyl, aryloxycarbonyl, thiol or thioether group. R1 and/or R2 are preferably aryl groups mono-substituted at the para position. The group R3 preferably represents a hydrogen atom, a halogen atom, for instance F, Cl, Br, I, a C1-C6 alkoxy or cycloalkoxy group, a C1-C6 alkyl or cycloalkyl group, a hydroxy group, an amino group of the formula xe2x80x94NR4R5 where R4 and R5 independently of one another represent a hydrogen atom, a C1-C6 alkyl or cycloalkyl group or a C6-C12 aryl, aralkyl or arylalkyl group, a group of the formula xe2x80x94CO2R6 where R6 represents a hydrogen atom (carboxyl groups), a C1-C6 alkyl or cycloalkyl group or a C6-C12 aryl, aralkyl or arylalkyl group (alkoxy and aryloxycarbonyl groups), a thiol group or a thiolether group of the formula xe2x80x94SR7 where R7 represents a C1-C6 alkyl or cycloalkyl group or a C6-C12 aryl, aralkyl or arylalkyl group, a nitrile group, an acyl group of the formula xe2x80x94(O)CR8 where R8 represents a C1-C6 alkyl or cycloalkyl group or a C6-C12 aryl, aralkyl or alkylarylgroup, or a nitro group.
The present invention further relates to a sulphonic acid of general formula I or a salt thereof, wherein R1 and R2 represent a (hetero)aryl group, optionally substituted with 1 to 5 substituents R3 wherein the groups R3 independently of one another are as defined above, it being understood that the compounds (a)-(o), as described above, are excluded.
According to the invention formula I in particular represents the following sulphonic acids or salts thereof, preferably in enantiomerically enriched form: 1,3-diphenyl-3-oxopropane-1-sulphonic acid, 3-phenyl-1-(4-methoxyphenyl)-3-oxopropane-1-sulphonic acid, 3-phenyl-1-(4-methylphenyl)-3-oxopropane-1-sulphonic acid or 3-phenyl-1-(4-fluorophenyl)-3-oxopropane-1-sulphonic acid.
The present invention also relates to a method of preparing the (d)- or (l)-enantiomer of a sulphonic acid according to the invention or a salt thereof, a compound of general formula II: 
being converted with MHSO3, where M may be alkali metal, an alkaline-earth metal or ammonium, to yield a compound of general formula I or a salt thereof, where R1and R2 have the above meanings, and the sulphonic acid of general formula I or the salt thereof being resolved into its (d)- and (l)-enantiomers using a resolving agent. The resolving agent may comprise more than one optically active compound that can form a complex, e.g. a salt or a conjugate, with the sulphonic acid or the salt thereof.
In this description a complex is understood to mean a compound in which the resolving agent and the enantiomer are bound to each other via for instance one or more covalent bonds, ionogenic bonds, coordination bonds, hydrogen bridges and/or a combination of such bonds.
Preferably, the resolving agent comprises an organic Brxc3x8nsted base, e.g. an amino functionalized compound, in particular an amine, an amino acid or a derivative thereof, for instance an ester or amide, an amino alcohol or an amino thiol. An optically active compound that is very suitable according to the invention is phenylglycine amide or p-methylphenylglycinol. This resolution in the preparation of the resolving agents involves the formation of a diastereomeric complex, in particular a complex of one enantiomer of the sulphonic acid according to the invention and the resolution agent. The invention, therefore, also relates to the diastereomeric complex of phenylglycine amide or p-methylphenylglycine and the sulphonic acid according to the invention. The conversion of such a diastereomeric complex into the enantiomers that are present in it is carried out according to known methods (for instance by treatment with acid or base followed by extraction, distillation or chromatography).
Preferably, M is an alkali metal, in particular sodium or potassium, or ammonium.
Applicant has found that the easily obtainable, anantiomerically enriched sulphonic acids according to the invention, are particularly suitable resolving agents. The present invention, therefore, further relates to the use of a (d)- or (l)-enantiomer of a sulphonic acid according to the invention or a salt thereof in the resolution of a mixture of enantiomers in a suitable solvent and to a diastereomeric complex comprising a sulphonic acid according to the invention and an enantiomerically enriched enantiomer, in particular a Brxc3x8nsted base, more particularly an amino-functionalized compound e.g. an amine, an amino acid or derivative thereof, an amino alcohol or an amino thiol. It is also possible as is described in EP-A-838448 to use two or more enantiomerically enriched sulphonic acids or a salts thereof, in particular (substituted) camphor sulphonic acids or (substituted) 1-phenylalkane sulphonic acids for the resolution of racemic mixtures and mixtures already having a certain enantiomeric excess.
The present invention therefore also relates to a method of preparing a resolving agent for the resolution of a mixture of enantiomers in a suitable solvent in which a resolving agent is added to a mixture of at least two sulphonic acids according to the invention or a salt thereof, this resulting in the formation of a mixture of diastereomers of the sulphonic acids and the resolving agent, and the mixture of diastereomers subsequently being resolved into a mixture of (d)-enantiomers of the sulphonic acid or the salt thereof, or a mixture of (l)-enantiomers of the sulphonic acid or the salt thereof. So, when for instance a racemic mixture of the enantiomers of sulphonic acid A and sulphonic acid B is resolved using a resolving agent X, this racemic mixture can be resolved into a mixture containing substantially the (d)-enantiomers of sulphonic acid A and sulphonic acid B or a mixture containing substantially the (l)-enantiomers of sulphonic acid A and sulphonic acid B.
It will be clear to one skilled in the art that mixtures substantially containing either two or more (d)-enantiomers or two or more (l)-enantiomers of a sulphonic acid or salt thereof, according to the invention are eminently suitable for use as resolving agent for the resolution of racemic mixtures as described in EP-A-838448. The invention therefore also relates to the use of such a resolving agent in the resolution of a mixture of enantiomers in a suitable solvent. These enantiomers are preferably an organic Brxc3x8nsted base, in particular an amino-functionalized compound, for instance an amine, an amino acid or a derivate thereof, for instance en ester or amide, an amino alcohol or an amino thiol.
The invention will be elucidated on the basis of the following examples.